Glioma intelligence from behind enemy lines

来自敌后的神经胶质瘤情报

基本信息

批准号：
10566235
负责人：
Terry Burns
金额：
$ 54.6万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566235
关键词：
Address Astrocytoma Biochemical Biology Brain Brain Neoplasms Catheters Cells Clinical Clinical Trials Combined Modality Therapy Cystathionine DL-alpha-Difluoromethylornithine Data Eflornithine Excision Feedback Genetic Genomics Glioblastoma Glioma Glutathione Glutathione Disulfide Human Image Implant In Situ Intelligence Investigational Therapies Knowledge Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Metabolic Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Microdialysis Modeling Molecular Molecular Weight Monitor Neurosurgical Procedures Ornithine Ornithine Decarboxylase Ornithine Decarboxylase Inhibitor Pathway interactions Patients Pharmacodynamics Phase Phenotype Polyamines Pre-Clinical Model Radiation Recurrence Reproducibility Resistance Safety Sampling Sorting Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stress Stromal Cells Testing Therapeutic Therapeutically Targetable Time Tissues Tumor Escape Up-Regulation Xenograft procedure blood-brain barrier disruption clinically relevant cohort experimental study extracellular gain of function guanidinoacetate human data improved outcome loss of function metabolome metabolomics neurosurgery novel novel strategies pharmacologic preclinical study promote resilience research clinical testing resilience stable isotope standard of care success targeted treatment translational progress tumor tumor growth uptake

项目摘要

Glioma intelligence from behind enemy lines Molecularly diverse gliomas may leverage convergent metabolic survival pathways that can be therapeutically targetable. Microdialysis enables sampling of the extracellular microenvironment and represents a previously underutilized opportunity to characterize and pharmacodynamically monitor living human gliomas, in situ. Our preliminary data from intraoperatively acquired glioma microdialysate reveal strong enrichment for methionine-associated pathways of cancer resiliency, including polyamine synthesis. Specifically, results to date have identified guanidinoacetate (GAA) as the most highly upregulated metabolite in glioma microdialysate, which we hypothesize results from upregulated polyamine synthesis within the tumor. This study will determine the reproducibility and potential therapeutic implications of our findings across a larger cohort of gliomas, asking if microdialysis could be leveraged to obtain mechanistic feedback during early phase clinical evaluation of candidate therapies. To interrogate methionine metabolism human gliomas in situ, we will perform intra-operative microdialysis and methionine tracing, comparing the metabolome of microdialysate and tissue from tumor and adjacent brain. Resected tissue will be used to determine the cellular source of methionine-associated metabolites. Recent studies have demonstrated that diverse tumors can escape DMFO-mediated polyamine metabolism by upregulation of polyamine transporters. Dual blockade of polyamine synthesis and polyamine transports with DMFO+AMXT 1501 has been shown to improve outcomes in preclinical models. To mechanistically interrogate polyamine metabolism we will perform a combination of preclinical and clinical studies leveraging microdialysis. In a phase 0 study, patients will be randomized to vehicle, DMFO, or DMFO+AMXT 1501, prior to dual administration of DMFO+AMXT to determine the extracellular pharmacodynamic changes induced by early therapeutic stress. Collectively, these studies will test how microdialysis can be used to perform biochemical reconnaissance within the live human glioma, with and without therapeutic challenge, to gain “glioma intelligence from behind enemy lines.”

来自敌后的神经胶质瘤情报分子多样化的神经胶质瘤可能会利用可治疗靶向的趋同代谢存活途径，从而能够对细胞外微环境进行采样，并且代表了以前未充分利用的原位表征和药效学监测活体人类神经胶质瘤的机会。富集与蛋氨酸相关的癌症恢复途径，包括多胺合成，具体而言，迄今为止的结果已鉴定出胍基乙酸盐。 (GAA) 是神经胶质瘤微透析液中上调程度最高的代谢物，我们从肿瘤内上调的多胺合成中寻找结果。这项研究将确定我们的研究结果在更大的神经胶质瘤队列中的可重复性和潜在的治疗意义，询问微透析是否可以用于治疗。为了在原位研究人胶质瘤的蛋氨酸代谢，我们将进行术中微透析和蛋氨酸。追踪、比较微透析液和来自肿瘤和邻近大脑的组织的代谢组将用于确定蛋氨酸相关代谢物的细胞来源，最近的研究表明，多种肿瘤可以通过上调多胺转运蛋白来逃避 DMFO 介导的多胺代谢。使用 DMFO+AMXT 1501 双重阻断多胺合成和多胺转运已被证明可以改善临床前模型的结果。对于多胺代谢，我们将利用微透析进行临床前和临床研究相结合。在 0 期研究中，患者将被随机分配至媒介物、DMFO 或 DMFO+AMXT 1501，然后再双重施用 DMFO+AMXT 以确定细胞外药效学变化。总的来说，这些研究将测试如何使用微透析在活体人类神经胶质瘤中进行生化侦察，无论有或没有治疗挑战，以获得收益。 “来自敌后的神经胶质瘤情报。”